PAracetamol and NSAID in Combination: A Randomised, Blinded, Parallel, 4-group Clinical Trial

Trial name: PAracetamol and NSAID in combination: A randomised, blinded, parallel, 4-group clinical trial

Trial acronym: PANSAID

Background: Effective postoperative pain management is essential for the well-being and rehabilitation of the surgical patient. No "gold standard" exists after total hip arthroplasty (THA) and combinations of different non-opioid medications are used with virtually no evidence for additional analgesic efficacy compared to monotherapy.

Objectives: The objective of this trial is to investigate the analgesic effects and safety of paracetamol and ibuprofen and their combination in different dosages after THA.

Intervention: Patients are randomised to 4 groups: A) paracetamol 1 g x 4 and ibuprofen 400 mg x 4; B) paracetamol 1 g x 4 and placebo (ibuprofen); C) placebo (paracetamol) and ibuprofen 400 mg x 4; and D) paracetamol 0,5 g x 4 and ibuprofen 200 mg.

Design: Placebo controlled, parallel 4-group, multicentre trial with adequate centralised computer-generated allocation sequence and allocation concealment with varying block size and stratification by site. Blinding of assessor, investigator, caregivers, patients, and statisticians.

Sample size: 556 eligible patients are needed to detect a difference of 10 mg morphine the first postoperative day with a standard deviation of 20 mg and a type 1 error rate of 0,004 (two-sided) and a type 2 error rate of 0,10.

Sub-studies: We preplan the following sub-studies. :

• A subgroup analysis of benefit outcomes (pain and opioid consumption) with respect to the following sub-groups: sex, age (below vs above 65 years old), ASA-score (I+II vs III), Use of analgesic medication before surgery (none vs any) and anaesthetic technique (general anaesthesia vs. spinal anaesthesia). Please find a detailed protocol at www.pansaid.dk
• A subgroup analysis of harm (serious adverse events and adverse events) with respect to the following groups sex, age (below vs above 65 years old), use of NSAIDs before surgery, and ASA-score (I+II vs III). Please find a detailed protocol at www.pansaid.dk
• Longer follow-up than the specified 90 days (1 year)
• An analysis of the association between VAS-scores and opioid consumption
• Time-to-event analyses regarding use of PCA-morphine
• An analysis of the association between preoperative analgesic use and pain/morphine consumption
• An analysis of the individual patients: how many will achieve "no worse than mild pain" (NRS<3). Please find a detailed protocol at www.pansaid.dk

More sub-studies may be performed post-hoc and they will be clearly identified as such.

Oversight of amendments and approvals Protocol version 2: Approved 12 August 2015: First approved version of the trial protocol

Protocol version 3: Approved 21 January 2016: Clarification of what happens in case of an SAE and definition of major protocol violations

Protocol version 4: Approved 15 June 2016: Clarification of the primary outcome, clarification that steroids are not permitted in the intervention period, and addition of an exploratory outcome (dizziness)

Protocol version 5: Approved 21 December 2016: Clarification of the exclusion criteria of contraindication to paracetamol and addition of stub-studies

Inclusion criteria

• Scheduled for unilateral, primary Total Hip Arthroplasty (THA)
• Age > 18
• ASA 1-3.
• BMI > 18 and < 40
• Women in the fertile age must have negative urine HCG pregnancy test
• Patients who gave their written informed consent to participating in the trial after having fully understood the contents of the protocol and restrictions.

Exclusion criteria

• Patients who cannot cooperate with the trial.
• Concomitant participation in another trial
• Patients who cannot understand or speak Danish.
• Daily use of strong opioids (tramadol and codein are accepted)
• Patients with allergy to the medicines used in the trial.
• Contraindications against NSAID, for example previous ulcer, heart failure, liver failure, or renal failure (eGRF < 60 ml/kg/1,73m2), known thrombocytopenia (<100 mia/L)
• Patients suffering from alcohol and/or drug abuse - based on the investigator's judgement.